Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C(O)(=O)C.[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N+:18]([O-])=O)[CH:9]=1.C(=O)([O-])O.[Na+]>[Fe].C(OCC)(=O)C>[NH2:18][C:10]1[CH:9]=[C:8]([Br:7])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1N
Temperature: 25 °C

Procedure:
2.6 g of iron powder was added to a mixed solution of 20 mL of methanol and 20 ml, of acetic acid containing 4.0 g of methyl 4-bromo-2-nitrobenzoate, and the resulting mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 2.0 g of methyl 2-amino-4-bromobenzoate as white solid.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C(#N)C.[F-].[K+].O>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:24]2[CH:2]=[CH:3][C:4]3[C:8]4[CH:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]=3[N:23]=2)=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Reactant: OCc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2ccc(-c3ccc(CO)cc3)nc21
Temperature: 140 °C
Yield: 172.5 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (700 mg, 0.87 mmol), 4-hydroxymethylbenzeneboronic acid (400 mg, 1.32 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.5 mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassium fluoride solution (21 mL) was devided equally across two 25 mL microwave vials. Each vial was degassed with nitrogen for 10 minutes before the mixtures were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixtures were allowed to cool to ambient temperature, combined and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (50 mL) and left to air dry. The resultant grey solid was purified by flash column chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane). The isolated solid was then triturated with hot t-BME to afford the title compound as a light grey solid (646 mg, 26%). LCMS (Method B): RT=4.11 min, M+H+=431.
Reaction SMILES: [CH2:1]=[O:2].CO.[CH2:5]([PH:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C(N(CC)CC)C>[CH2:5]([P:8](=[O:12])([CH2:9][CH2:10][CH3:11])[CH2:1][OH:2])[CH2:6][CH3:7]
Reactant: C=O
Reactant: CCC[PH](=O)CCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCP(=O)(CO)CCC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 37% of formaldehyde solution, 16.2 g, was added in small portions over a five minute period to solution of 40 ml of methanol, 21.78 g of di-n-propyl phosphine oxide, (Example 16), and 1.5 ml of triethylamine. The reaction exothermed to 30° C. and was allowed to stir for ten minutes before it was warmed to 70° C. for three hours. The reaction was then allowed to cool to room temperature and stand overnight. The reaction was concentrated, the concentrate dissolved in 70 ml of THF, filtered and reconcentrated. The concentrate was diluted with 60 ml of 1,4-dioxane which was distilled off to yield 19.8 g of the desired phosphine oxide as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2oc3ccc(C(=O)CCCCl)cc3c2c1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A mixture of 17.0 g (0.045 mole) of 2,8-bis(4-chlorobutyryl)dibenzofuran, 68.0 g (0.8 mole) of piperidine and 2.0 g of potassium iodide in 500 ml of butanone is heated at reflux for 72 hours then filtered. The filtrate is concentrated to one-half its original volume then diluted with 600 ml of water. The resulting semi-solid is purified by chromatography on neutral alumina using methylene chloride as the eluant. The solvent is removed from the fraction collected leaving a solid residue which is recrystallized from pentane to give 2,8-bis(4-piperidinobutyryl)dibenzofuran, M.P. 70°-71° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:23]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:18]3[C:17]([NH:43][CH:44]3[CH2:48][C:47](=[O:49])[N:46](CC4C=CC(OC)=CC=4)[CH2:45]3)=[N:16]2)=CC=1.C(Cl)[Cl:62]>>[ClH:62].[C:37]1([C:22]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[C:18]3[C:17]([NH:43][CH:44]4[CH2:45][NH:46][C:47](=[O:49])[CH2:48]4)=[N:16][NH:15][C:19]3=[N:20][CH:21]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClCCl
Reactant: COc1ccc(CN2CC(Nc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1CC(Nc2n[nH]c3ncc(-c4ccccc4)c(N4CCNCC4)c23)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
TFA (0.52 mL, 6.79 mmol) was added to a solution of tert-butyl 4-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-5-oxopyrrolidin-3-ylamino)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.195 g, 0.27 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in TFA (4 mL) and heated at 100° C. in a sealed tube overnight. The TFA was removed. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL) was added. The solid formed was collected by filtration to give 4-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)pyrrolidin-2-one hydrochloride (0.20 g, 98% yield) as a solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Brc1ccccn1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccccn4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromopyridine
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:9](=[CH2:11])=[N-:10].C(O)(=O)C>C(OCC)C>[N+:9](=[CH:11][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N-:10]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)CC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl acetyl chloride (1.136 grams) in dry ethyl ether (10 mL) was slowly added to a 0° C. diethyl ether (20 mL) solution of freshly generated diazomethane (from 20 grams Diazald). After stirring for 30 minutes, the reaction was warmed to ambient temperature for another 30 minutes. Acetic acid (2 mL) was added and the reaction partitioned between methyl tert-butyl ether and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Concentration afforded an oil containing the title compound which was immediately used with no further purification.
Reaction SMILES: ClC(Cl)C.[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32].[C:35](OC(=O)C)(=[O:37])C>[Pd].C(O)=O>[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([NH:22][CH:35]=[O:37])[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: O=CO
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 ml of dichloroethane and 10 ml of formic acid were added 2 g of ethyl 8-chloro-6,7-difluoro-1-(2,4-difluoro-5-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 200 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred at room temperature for 3 hours and after addition of acetic anhydride, further stirred overnight. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with ethanol and diethyl ether to give 1.9 g of the title compound.
Reaction SMILES: [C:1](OCC)(=[O:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C[AlH]CC(C)C)C.C(OCC)C>CCCCCCC.[Cl-].[Na+].O>[CH2:1]([OH:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC/C=C/C=C/C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: O
Product: CCCCCCC/C=C/C=C/CO
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Under nitrogen atmosphere, (2E,4E)-ethyl dodeca-2,4-dienoate (6.1 g) was dissolved in n-heptane (120 ml) and cooled to −70° C. DIBAL-H in hexanes (82 ml) was added dropwise and the mixture was stirred at −70° C. for 45 min. Brine (60 ml) and diethyl ether (100 ml) were added and the mixture was stirred for 45 min while warming to RT. The organic layer was separated and washed with 1N HCl, dried over sodium sulfate, filtered and concentrated. A colorless liquid was isolated that solidified upon slight cooling.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1COCC1.CCO>O>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of Na2S2O4 (34.8 g, 200 mmol) in H2O (200 mL) was added to a mixture of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (16.0 g, 64.7 mmol), THF (150 mL), and EtOH (150 mL), and the mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (5.84 g, 42% yield) as a light brown oil: 1H NMR (300 MHz, CDCl3): δ ppm 3.42 (2H, brs), 4.97 (2H, s), 6.60 (1H, ddd, J=1.1, 2.6, 8.7 Hz), 6.67-6.74 (2H, m), 7.28-7.43 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([Mg]Br)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(OCC)C>[CH2:20]([O:19][C:17]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2ccc(OC)cc12
Temperature: -5 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of 5-methoxyindole (10.0 g, 67.9 mmol) in anhydrous diethyl ether (200 cm3) being maintained at 0° C. under a nitrogen atmosphere was added a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 22.65 cm3, 67.95 mmol) over a period of ca. 10 min. The reaction was heat to reflux for 45 min, cooled to −5° C. and ethyl chloroformate (6.5 cm3, 67.9 mmol) was added. After stirring at this temperature for 1 h, the mixture was heated to reflux for 30 min, cooled and added to ice containing sat. aqueous ammonium chloride solution (150 cm3). This mixture was extracted into ethyl acetate (150 cm3), washed with water (3×150 cm3), dried (MgSO4) and evaporated under reduced pressure to afford a brown oil (13.21 g), crystallisation from diethyl-ether/heptane afforded the title compound (4.95 g, 33%). Positive ion ESI (M+H)+ 220.0.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccc3)CN2C1=O
Yield: 15.3 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and benzoyl chloride (41 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 18 mg (15%) of 18-benzoyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 97.0% pure (HPLC), MS m/z 673 (M+H)+, HRMS: calcd. 673.2907 and found 673.2908 (M+H)+, mp 140-142° C.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][CH:3]=[C:2]1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl[C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1.[NH2:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]1>>[CH3:22][C:18]1[C:17]([C:11]2[S:10][C:9]([C:2]3[S:1][C:5]([C:6](=[O:8])[CH3:7])=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:16][C:15]([NH:23][CH:24]2[CH2:25][C:26]([CH3:33])([CH3:32])[NH:27][C:28]([CH3:31])([CH3:30])[CH2:29]2)=[N:20][CH:19]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(=O)c1ccc(-c2cccs2)s1
Product: CC(=O)c1ccc(-c2ccc(-c3nc(NC4CC(C)(C)NC(C)(C)C4)ncc3C)s2)s1

Procedure:
The title compound was prepared analogous to Method A, starting from 1-[2,2′]bithiophenyl-5-yl-ethanone, 2,4-dichloro-5-methyl-pyrimidine and 4-amino-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1[NH:8][N:9]=[C:10]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[C:6]=1[CH2:5]2.BrC1C=C2C(=CC=1)CCC2.[CH3:36][N:37](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[C:10]1[NH:9][N:8]=[C:7]2[C:23]3[C:4]([CH2:5][C:6]=12)=[CH:3][C:2]([C:36]#[N:37])=[CH:25][CH:24]=3
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1-c1n[nH]c2c1Cc1cc(Br)ccc1-2
Agent: Brc1ccc2c(c1)CCC2
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1cc(C#N)ccc1-2
Temperature: 80 °C
Yield: 13 %

Procedure:
A suspension of 6-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-1,4-dihydroindeno[1,2-c]pyrazole (500 mg, 1.3 mmol) (prepared from 5-bromoindane in the same manner as Example 1) and zinc cyanide (912 mg, 7.8 mmol) in DMF (5 ml) was degassed with N2 for 0.5 hr, tetrakis(triphenylphosphine)palladium(0) (100 mg) was added and heated to 80° C. for 3 days. The reaction mixture was cooled, poured into 10% ammonium hydroxide solution and extracted into EtOAc. The organic layer was washed with H2O(×3) then dried (MgSO4), evaporated and the residue chromatographed on silica, eluting with dichloromethane and recrystallised from hot dichloromethane to give the title compound as a white solid (55 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 2H), 7.51–7.37 (m, 5H), 3.35 (s, 2H), 2.59 (s, 3H), m/z (ES+) 339 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=O.Cl.[CH3:17][O:18][NH2:19].C(=O)([O-])[O-:21].[K+].[K+]>O1CCCC1>[CH3:1][C:2]([CH3:15])([CH:14]=[O:21])[CH2:3][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:19][O:18][CH3:17])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: CON
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(CC(C)(C)C=O)cc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of 67.2 grams of 4-(2,2-dimethyl-1-oxopropyl)-benzoyl chloride dissovled in 100 millimeters of tetrahydrofuran (THF) is added dropwise to a suspension of 25.0 grams of methoxyamine hydrochloride and 256 grams of finely ground anhydrous potassium carbonate in 1.1 liters of THF. The reaction mixture is stirred at 23° C. overnight and then heated to 50° to 55° C. for 5 hours. This mixture is cooled to room temperature and filtered. The residue is washed with THF, and the filtrates are combined and evaporated to dryness. The crude product is partitioned between 200 ml of chloroform and 200 ml of cold 1 molar sodium carbonate solution, following which the organic phase is separated from the aqueous phase, dried with magnesium sulfate and evaporated to dryness. The residue is recrystallized twice from methylene chloride/t-butyl methyl ether to yield the pure title compound (mp 126°-127.5° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20]2)=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:42]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:42]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[F:36])=[N:4][C:3]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]1)=[O:11]
Reactant: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Reactant: OB(O)c1ccncc1F
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cc(F)c(-c2ccncc2F)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N)C1

Procedure:
A solution of 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 3-fluoropyridin-4-yl-boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, 5-amino-N-(4-((1R,3S)-3-aminocyclohexyl)-pyridin-3-yl)-3,3′-difluoro-2,4′-bipyridine-6-carboxamide as the TFA salt. LCMS (m/z): 425.1 (MH+); LC Rt=2.08 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[CH3:18])=[O:15].O[Li:35].O>>[F:32][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1)[CH3:18])=[O:15].[Li+:35]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(OC(F)(F)F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCCN1Cc1cccc(OC(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E8) (51 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-(trifluoromethoxy)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D25) (52 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.Br[C:9]1(O)[CH:14]=[CH:13][CH:12]=[CH:11][NH:10]1.COCCO[AlH2-]O[CH2:23][CH2:24][O:25]C.[Na+]>C1(C)C=CC=CC=1>[C:23]1([C@H:24]([O:25][C:14]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:3]2[O:4][CH2:5][CH2:6][NH:1][CH2:2]2)[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1COCCN1
Reactant: OC1(Br)C=CC=CN1
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc([C@H](Oc2cccnc2)[C@@H]2CNCCO2)cc1
Temperature: 0 °C

Procedure:
(S)-2-[(S)-Phenyl-(pyridin-3-yloxy)-methyl]-morpholine was synthesized from the corresponding amide (6-[Phenyl-(pyridin-3-yloxy)-methyl]-morpholin-3-one) (see Scheme G, compound 8) using the following procedure: A solution of compound 1 (0.30 g, 0.85 mmol) in anhydrous toluene (3.0 mL) was placed under a nitrogen atmosphere, cooled to 0° C. and a commercial solution of Red-Al (65 wt % in toluene, 1.0 mL, 3.3 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature over 4 h. TLC analysis showed no starting material remaining. The reaction mixture was again cooled to 0° C. and quenched by the dropwise addition of 2N sodium hydroxide. The reaction mixture was diluted with toluene, the aqueous phase separated and further extracted with toluene. The combined organic extracts were dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to give 0.30 g of light brown oil. Two chromatographies of the reaction product on silica gel (eluent—3:1 ethyl acetate/methanol the second) gave 0.080 g (35%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 8.12 (m, 1H), 7.24 (m, 5H), 7.10 (m, 2H), 5.10 (d, 1H), 3.96 (m, 2H), 3.68 (m, 1H), 2.84 (m, 2H), 2.66 (m, 2H), 1.84 (br s, 1H). (MS) m/z 271.05 [C16H18N2O2+H+]; CHN—C16H18N2O2 Calc'd: C, 71.09%; H, 6.71%; N, 10.36%. Found: C, 70.49%; H, 6.70%; N, 9.83%.